This invention relates to novel thiourea compounds for use in personal care product applications, such as skin care and hair care products, to protect the skin and hair from degradation caused by free radical polymerization and oxidation.
Skin and hair are exposed to a variety of environmental factors that tend to degrade it. These include but are not limited to sun exposure, exposure to ozone, smog and other airborne pollutants. These conditions cause the skin to wrinkle, dry out, turn scaly and in extreme cases develop disease states like melanoma. Hair becomes brittle and dry and is cosmetically unappealing. The present invention relates to a new series of free radical inhibitors that protect the skin and hair from the deleterious effects of these environmental conditions.
The ultraviolet (UV) wavelengths of sunlight can cause sunburn (erythema) and blistering (edema). Exposure to ultraviolet light can also cause the skin to feel dry and taut in moderate doses, and to peel if exposed to higher doses. These acute, or short term, effects are readily perceptible and oftentimes uncomfortable and painful. While the exposure of the skin to the damaging effects of the sun can cause potential health problems, the exposure of hair to the sun can cause the hair to become dehydrated, weakened, and, in some instances, bleached. Hair that is damaged by sun exposure may become cosmetically unacceptable.
Human skin can be protected from some of these environmental effects. Moisturizers can readily reverse the appearance of dryness regardless of whether it results from low humidity conditions or UV light, and relieve the tautness of the skin caused by UV light exposure. These products either attract moisture from the environment to the skin""s surface, or reduce the amount of evaporative loss from the surface of the skin. These products also add needed moisture to the skin from the formulation itself, and add a layer of emollients on the skin surface to leave it softer and more supple.
According to the free radical theory of premature aging of the skin, ultraviolet light can produce reactive oxygen species (ROS) that damage the skin. ROS are a collection of reactive free radicals produced from the oxygen molecule, and include singlet oxygen, the superoxide radical, hydrogen peroxide, and the hydroxyl radical, as well as the reaction products produced by these free radicals. Due to their reactivity, ROS relatively indiscriminately react with other molecules, and generate a cascade of harmful free radical reactions in the skin.
The skin possesses certain defense mechanisms against the generation of ROS. These defenses include the presence of enzymes such as superoxide dismutase, catalase, glutathione transferase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as tocopherols, ubiquinone, ubiquinol, ascorbic acid and dehydroascorbic acid. Unfortunately, ultraviolet light entering the skin can easily overwhelm these defense systems, such that the amount of superoxide dismutase and glutathione transferase in the skin declines significantly upon irradiation with solar ultraviolet light. Simultaneous with the loss of these reducing enzymes, there is a dramatic increase in conjugated double bonds formed in the skin from the linoleates present in cell membranes. There is also an increase in thiobarbituric acid reactive substances present in the skin, which represent a collection of molecules that are formed from ROS.
Since sunscreens are unable to completely protect the skin against the adverse effects of ultraviolet radiation, alternative modes of protection have been proposed. Vitamins, such as Vitamin E acetate, have been shown to make the skin softer and smoother after topical application, which can offset some of the damaging effects of the sun. Vitamin A palmitate has been shown to create smoother skin and help enhance the process of cellular turnover. This enhancement rids the skin of the outermost dead layer of skin by bringing more youthful appearing skin cells to the surface. Other materials, such as hyaluronic acid and pyrrolidone carboxylic acid (PCA), have also been used for their ability to enhance the moisture binding capacity of the skin and therefore lead to smoother, softer skin.
Compositions that incorporate Vitamins A or E, or their derivatives, in sunscreen compositions, are shown in U.S. Pat. Nos. 4,454,112; 5,532,805; and 5,378,461. The use of Vitamin C in combination with Vitamins A, E, B and other agents in a skin protectant composition, is described in U.S. Pat. No. 4,938,960. An antioxidant preparation that is said to protect the skin against harmful ultraviolet radiation is disclosed in U.S. Pat. No. 5,607,921, and contains Vitamin C, in combination with Vitamins A and E, and monosaccharide or amide precursors. Sunscreen compositions containing panthenol and other agents are disclosed in U.S. Pat. Nos. RE 33,845; 5,505,935; 5,445,823; and 5,573,754. The antioxidant effect of superoxide dismutase when externally applied to the skin to protect against the effects of ultraviolet radiation is also described in U.S. Pat. No. 5,601,806.
In spite of advances in recent years in the protection of skin from harmful ultraviolet radiation, the epidemic of skin cancer and skin damage from the effects of this radiation has continued unabated. The loss of portions of the ozone layer from environmental pollution is believed to have contributed to an increase in ambient ultraviolet radiation that reaches exposed skin. There is a significant need for commercially acceptable or improved preparations that can be topically applied expecially to human and animal skin, to offset the harmful effects of ultraviolet radiation.
The present invention relates to the discovery that certain 1-(3-methoxybenzyl)-3-substituted thiourea compounds and compositions containing same, when applied topically to the skin or hair of a human or nonhuman animal, inhibit free radical degradation (i.e., degradation caused by free radical polymerization of natural compounds present in skin tissue or hair), and oxidation of the skin or hair. The 1-(3-methoxybenzyl)-3-substituted thiourea compounds are soluble in oils and alcohols and the like, and may desirably be provided in an oil based composition, or in the oil phase of an emulsion, which can be applied to the skin or hair.
The present invention thus entails a method for protecting skin or hair from free radical polymerization and degradation, which comprises contacting the skin or hair with a concentration of a 1-(3-methoxybenzyl)-3-substituted thiourea compound of formula I which is effective to inhibit free radical polymerization, 
wherein R is a C1-C20 linear or branched alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, decyl, nonyl, dodecyl, and the like, C5-C7 cycloalkyl, such as cyclopentyl, cyclohexyl or cycloheptyl and the like, C6-C7 aryl such as phenyl or benzyl and the like, hydroxy- or alkoxy-substituted C6-C7 aryl such as hydroxyphenyl, methoxyphenyl, ethoxyphenyl, hydroxybenzyl, methoxybenzyl or ethoxybenzyl. Among compounds of the formula I, a presently preferred free radical inhibiting compound is 1,3-di(3-methoxybenzyl) thiourea, i.e., a compound of formula I wherein R is a 3-methoxybenzyl moiety. The compound, 1,3-di(3-methoxybenzyl) thiourea, has been identified as an antioxidant in meadowfoam seed oil as disclosed in U.S. Provisional Patent Application No. 60/202562, filed May 10, 2000, which is incorporated herein by this reference.
The present invention also provides skin treatment compositions comprising between about 0.01 wt. % and about 5 wt. %, preferably between about 0.1 wt. % and about 2 wt. %, of a free radical inhibiting compound of formula I in an appropriate base composition such as a moisturizing composition, skin lotion, sunscreen lotion, sunblock lotion, or the like. Hair treatment compositions are also provided which comprise between about 0.01 wt. % and about 5 wt. %, preferably between about 0.1 wt. % and about 2 wt. %, of a free radical inhibiting compound of formula I in an appropriate base composition such as a hairspray, gel, mousse or the like. As used herein, the term xe2x80x9cbase compositionxe2x80x9d includes cosmetic base compositions for skin and base compositions for hair which may be conventionally provided as oils, oil-in-water emulsions, water-in-oil emulsions, oil-in-water-in-oil (O/W/O) emulsions, microemulsions, gels or the like.
Presently preferred compounds of formula I for use in accordance with the present inventions are 1,3-di(3-methoxybenzyl) thiourea; 1-(3-methoxybenzyl)-3-ethyl-2-thiourea; 1-(3-methoxybenzyl)-3-propyl-2-thiourea; 1-(3-methoxybenzyl)-3-hexyl-2-thiourea; 1-(3-methoxybenzyl)-3-dodecyl-2-thiourea; 1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea; and 1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea. The free radical inhibiting activity of the compounds of formula I diminish the deleterious effects of environmental factors when applied to the skin alone, or desirably in combination with one or more sunscreen compositions. 1,3-di(3-methoxybenzyl) thiourea is a particularly preferred free radical inhibitor compound. Meadowfoam seed oil may be used as an ingredient in emulsion or the like to provide an effective free radical inhibitor concentration of 1,3 di(3-methoxybenzyl) thiourea.
In one of its aspects, the present invention entails a method of protecting the skin or hair of a human or nonhuman animal from free radical degradation comprising contacting the skin or hair with an amount of a 1-(3-methoxybenzyl)-3-substituted thiourea compound of the formula I 
in a concentration which is sufficient to inhibit free radical degradation wherein R is selected from the group consisting of C1-C20 linear or branched alkyl; C5-C7 cycloalkyl; alkoxy-substituted C5-C7 cycloalkyl; hydroxy-substituted C5-C7 cycloalkyl; C6-C7 aryl; hydroxy-substituted C6-C7 aryl; and alkoxy-substituted C6-C7 aryl. In a particularly preferred embodiment, the substituted aryl moiety is a 3-hydroxy-substituted or 3-alkoxy-substituted aryl compound.
In another of its aspects, the present invention entails a skin treatment composition or hair treatment composition capable of inhibiting free radical degradation of the skin or hair, which comprises a skin cosmetic base composition or hair cosmetic base composition, which contains a concentration of a 1-(3-methoxybenzyl)-3-substituted thiourea compound of the formula I 
which is effective to inhibit free radical degradation of the skin or hair, wherein R is selected from the group consisting of C1-C2 linear or branched alkyl; C5-C7 cycloalkyl; hydroxy- or alkoxy-substituted C5-C7 cycloalkyl; C6-C7 aryl; and hydroxy- or alkoxy-substituted C6-C7 aryl. The skin or hair treatment composition of the invention may optionally be supplemented with one or more conventional sunscreen compositions, vitamins, or other compounds useful for protecting skin or hair from the degradative effects of ultraviolet radiation. The novel thiourea derivatives according to formula I are described in U.S. Provisional Patent Application No. 60/202562, filed May 10, 2000, which is incorporated herein by this reference.
As used herein, xe2x80x9cC1-C20 linear or branched alkylxe2x80x9d shall include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, 2-methyl-pentyl, 3-methyl-penyl, hexyl, octyl, decyl, dodecyl, and the like. The term xe2x80x9cC5-C7 cycloalkylxe2x80x9d shall include cyclopentyl, cyclohexyl and cycloheptyl. The term xe2x80x9chydroxy- or alkoxy-substituted C5-C7 cycloalkylxe2x80x9d shall include cyclopentyl, cyclohexyl and cycloheptyl moieties that are substituted with an hydroxy, methoxy, ethoxy, or propoxy group or the like. The term xe2x80x9cC6-C7 arylxe2x80x9d shall include phenyl and benzyl. The term xe2x80x9chydroxy- or alkoxy-substituted C6-C7 arylxe2x80x9d shall include phenyl and benzyl moieties that are substituted with an hydroxy, methoxy, ethoxy, or propoxy group or the like.
Compounds of the formula I may be synthesized by reacting 3-methoxybenzylamine and an appropriately selected isothiocyanate compound of the formula II Sxe2x95x90Cxe2x95x90Nxe2x80x94R, wherein R is defined the same as for compounds of formula I. The reaction may be carried out by slowly adding the isothiocyanate to an aqueous solution of 3-methoxybenzylamine, preferably under a nitrogen atmosphere. The thiourea product of the reaction, which is a compound of formula I, may be recovered and purified by mixing the reaction products with a solvent that is not miscible with water but one that is a solvent for the thiourea, such as methylene chloride, chloroform, toluene or diethyl ether. The water layer may or may not be acidified to enhance separation and recovery of the thiourea compound of the invention. The thiourea, dissolved in the solvent layer can be drawn off from the water layer, dried and the resulting crude thiourea purified by recrystallization in an appropriate solvent such as ethanol. See, Example 1. See also, generally, the procedure of Moore and Crossley, Organic Synthesis 2, 617-618 (note 4).
The reactants, 3-methoxybenzylamine and an appropriate isothiocyanate compound as defined above, may be obtained commercially or synthesized by routine methods known in the art, and the resultant product compounds of formula I may be readily isolated by routine methods well-known to those having ordinary skill in the art. Suitable isothiocyanate reactants for synthesizing compounds of the present invention may be obtained as well-known in the art from degradation of glucosinolates present in seed oils and other lipids. In an aqueous solution containing the enzyme thioglucosidase, glucosinolate compounds are degraded into isothiocyanates and other degradation products. See, Vaughn, et al., J. Chem. Ecol. 22, 1939-49 (1996); and C. VanEtten and H. Tookey, (1983) Glucosinolates, pp. 15-30 in M. Rechcigl (ed.) xe2x80x9cNaturally Occurring Food Toxicants,xe2x80x9d CRC Press, Boca Raton, Fla. The isothiocyanate fraction of the glucosinolate breakdown products thus may be isolated and reacted with 3-methoxybenzylamine as described above to provide compounds of the present invention. Approximately 100 glucosinolate compounds have been identified in plants from 11 different plant families including mustard, rapeseed, cabbage, garlic mustard and crambe (S.F. Vaughn, 1999. Glucosinolates as Natural Pesticides in Biologically Active Natural Products: Agrochemicals, H. G. Cutler and S. J. Cutler, Eds, CRC Press, Boac Raton, Fla.) Oils isolated from glucosinolate containing plants are normally deodorized by steam sparging to remove volatile compounds which includes isothiocyanates and amines. Thus, a variety of isothiocyanate compounds and benzylamine compounds may be obtained from the waste distillation product generated in the process of purifying such oils and employed as reactants in synthesizing compounds of the present invention.
3-methoxybenzylamine may be purchased commercially or may be isolated from meadowfoam seed oil by extraction into an immiscible acidified aqueous layer which is separated from the oil, washed with a nonpolar solvent, treated with a base to lower pH, and the amine extracted into an immiscible solvent. The 3-methoxybenzylamine compound may be further purified by crystallization from ethanol or similar solvent and/or purified by reverse-phase HPLC using a C18 column, eluting with a gradient starting at 100% methanol and proceeding to about 80% methanol:20% chloroform. The peak containing 3-methoxybenzylamine may be identified by its retention time on the HPLC column in comparison to the retention time for a known standard sample of 3-methoxybenzylamine. Other natural amines may be purchased commercially or may be similarly extracted from natural sources and purified with reference to known standard samples and/or identified by standard chemical methods for identification of amines (e.g., chromatography, infrared spectroscopy, mass spectroscopy, elemental analysis, nuclear magnetic resonance analysis and the like).
The phrase xe2x80x9can effective concentration of a free radical inhibitorxe2x80x9d or xe2x80x9cconcentration which is effective to inhibit free radical degradationxe2x80x9d as used herein means a concentration of a free radical inhibitor compound that is capable of reducing the amount of free radical polymerization of a polymerizable compound as compared to the amount of free radical polymerization obtained in the absence of the free radical inhibitor compound. Methods of determining the ability of a compound to inhibit a free radical polymerization reaction are well known in the art.
A presently preferred method for determining the free radical inhibitory capacity of a compound is based on the ability of such a compound to inhibit free radical polymerization of acrylic acid to polyacrylic acid. A suitable assay for demonstrating an effective concentration of a selected free radical inhibitor compound is an assay which determines the ability of such a compound to inhibit the polymerization of a 30% aqueous solution of acrylic acid at 85xc2x0 C. after initiation with 0.1% azobisisobutyrylnitrile. The inhibitory capacity of such a compound is determined by comparing the percent of polyacrylic acid formed in the presence and absence of a predetermined concentration of the selected free radical inhibitor compound, with inhibition being demonstrated by a detectable decrease in the amount of polyacrylic acid formed in the reaction mixture containing the inhibitor as compared to the amount of polyacrylic acid formed in the reaction mixture to which an inhibitor was not added. As will be appreciated, the amount of polyacrylic acid formed is inversely related to the amount of acrylic acid (i.e., monomer) remaining in the reaction mixture at the end of the assay. The amount of acrylic acid may be routinely determined by measuring the iodine value of the reaction mixture or by other methods known in the art for determinating unsaturation. A well-known free radical inhibitor compound such as hydroquinone mono methyl ether (HQMME) may be used as a standard inhibitor compound in the assay.
The compounds of formula I herein are potent inhibitors of free radical polymerization, as well as scavengers of hydroperoxides which are known precursors to free radicals. The compounds of formula I also desirably absorb UV radiation at a wavelength of 280 nm. Due to their ability to inhibit free radical degradation, the compounds of formula I are capable of imparting free radical inhibition activity to the skin or hair in accordance with the methods of the present invention. Free radical degradation can be initiated and propogated even in the presence of an effective sunscreen composition. Thus, in one embodiment of the present invention, skin care compositions contain an effective concentration of a compound of formula I sufficient to inhibit free radical degradation, as well as an effective concentration of a sunscreen composition for absorbing UV light. The free radical inhibitor compounds of formula I and the sunscreen compounds have activities that are complementary to one another. Among the well known sunscreen compositions (and the preferred percentages (w/w) that provide effective sunscreen protection), which may be used in accordance with the present invention, are UVA absorbers, including oxybenzone (2-6%), sulisobenzone (5-10%), dioxybenzone (3%), methyl anthranilate (3.5-5%), UVB absorbers, including aminobenzoic acid (5-15%), amyldimethyl PABA (1-5%), 2-ethoxyethyl p-methoxycinnamate (1-3%), diethanolamine p-methoxycinnamate (8-10%), digalloyl trioleate (2-5%), ethyl 4-bis(hydroxypropyl) aminobenzoate (1-5%), 2-ethylhexyl-2-cyano-3,3-diphenylacrylate (7-10%), ethylhexyl p-methoxycinnamate (2-7.5%), 2-ethylhexyl salicylate (3-5%), glyceryl aminobenzoate (2-3%), homomenthyl salicylate (4-15%), lawsone with dihydroxyacetone (0.25% with 33%), octyldimethyl PABA (1.4-8%), 2-phenylbenzimidazole-5-sulfonic acid (1-4%), triethanolamine salicylate (5-12%), and the physical UV absorbers, red patrolatum (30-100%) and titanium dioxide (2-25%).
The free radical inhibiting compounds, alone or in combination with a suitable suncreen compound, may be included into a variety of skin care or hair care compositions. It is presently contemplated that the free radical inhibitor compounds of formula I will be dissolved in an oil, lipid or alcohol which is used to prepare a skin treatment composition or a hair treatment composition of the invention. Suitable base compositions for preparing the skin or hair treatment compositions of the invention include lotions, liquids, creams, ointments, and the like, which may be conventionally provided as oils, oil-in-water emulsions, water-in-oil emulsions, oil-in-water-in-oil emulsions, microemulsions, liposomes or the like as are well known in the art. Various compositions useful for skin treatment or for hair treatment, which can be used (with or without the sunscreen compositions being added) to deliver compounds of formula I to the skin or hair may be prepared from the disclosures in for example, U.S. Pat. Nos. 4,115,547; 4,172,122; 4,454,112; 4,567,038; 4,592,906; 4,663,157; 4,847,267; 4,938,960 and 5,980,871. The Examples that follow provide skin treatment compositions of the invention including free radical inhibitor compounds of the formula I.
The following nonlimiting examples are illustrative of the invention.